Metabolic adaptation is likely an essential component of cancer development and progression. Tumors use a variety of strategies to fulfill their metabolic needs, including but not limited to aerobic glycolysis also known as the Warburg effect. Moreover, emerging data suggest that metabolic differences also exist within the same cancer type, for example, Diffuse Large B-cell Lymphoma (DLBCL), a highly heterogeneous disease that accounts for ~40% of lymphoid malignancies in adults. Our laboratory has recently carried out an integrative analysis of metabolic profiles in genetically defined subsets of DLBCLs, which revealed striking and previously unappreciated differences in nutrient utilization pathways that may contribute to DLBCL proliferation and survival. Understanding the molecular mechanisms underlying this metabolic heterogeneity may not only shed light on novel pathways that contribute to lymphoma genesis but also uncover potential therapeutic targets as well as novel diagnostic tools for patient stratification. Among the genetically defined subsets of DLBCL, the oxidative phosphorylation (OxPhos) subtype displays marked elevation of mitochondrial electron transport chain (ETC) activity without increased production of reactive oxygen species (ROS), a known respiratory byproduct. In this proposal I seek to understand the nature of homeostatic pathways that account for increased functional quality of mitochondria in this subset. My preliminary data suggest that mitochondrial quality control mechanisms, including autophagic clearance of sub-optimal ROS-producing mitochondria and regulated assembly of mitochondrial ETC complexes may be selectively up-regulated in OxPhos-DLBCLs. These observations give rise to the hypothesis that functional efficiency of mitochondria in OxPhos-DLBCLs may be linked to higher quality control of the mitochondrial pool. I will test this hypothesis through the following specific aims: Aim 1 evaluates the contribution of mitochondrial turnover through enhanced mitochondrial autophagy (mitophagy) to overall metabolic function, ROS homeostasis and cell viability in the OxPhos-subset of DLBCL. Enhanced mitochondrial turnover is expected to serve as a mechanism to clear damaged, suboptimal and high ROS- generating mitochondria, thus ensuring a healthier mitochondrial pool in OxPhos-DLBCLs. Aim 2 investigates the factors responsible for efficient assembly and maintenance of the ETC machinery. Elevated ETC activity is a defining characteristic of the OxPhos-subset of DLBCL, therefore it is predicted that mitochondrial proteases, chaperones and the morphology of the inner mitochondrial membrane where the ETC machinery resides contribute to the increased respiratory efficiency observed in OxPhos-DLBCLs. The scope of the factors investigated in this aim will be limited to a short list of mitochondrial proteins that based on my preliminary data, are selectively up-regulated in OxPhos-DLBCLs compared to other DLBCL subtypes. The aims outlined in this proposal may provide the foundation for future rationale drug targets for OxPhos- DLBCLs. In addition this study may reveal useful insights into the molecular underpinnings of metabolic heterogeneity in other types of cancer. PUBLIC HEALTH RELEVANCE: Within the group of cancers falling under the diagnosis of Diffuse Large B-cell Lymphoma, there is a distinct subset that relies on mitochondrial function to satisfy nutrient and energy demands. This study will investigate cellular pathways specifically required by this subset of Diffuse Large B-cell Lymphoma for the maintenance of mitochondrial quality and function. A better understanding of mitochondrial maintenance pathways in this disease may provide insight into future targeted therapies for this subset of Diffuse Large B-cell Lymphoma as well as other cancers that display a similar metabolic profile.